Aurora-A-dependent control of TACC3 influences the rate of mitotic spindle assembly

The essential mammalian gene TACC3 is frequently mutated and amplified in cancers
and its fusion products exhibit oncogenic activity in glioblastomas. TACC3 functions in
mitotic spindle assembly and chromosome segregation. In particular, phosphorylation
on S558 by the mitotic kinase, Aurora-A, promotes spindle recruitment of TACC3 and
triggers the formation of a complex with ch-TOG-clathrin that crosslinks and stabilises
kinetochore microtubules. Here we map the Aurora-A-binding interface in TACC3 and
show that TACC3 potently activates Aurora-A through a domain centered on F525.
Vertebrate cells carrying homozygous F525A mutation in the endogenous TACC3 loci
exhibit defects in TACC3 function, namely perturbed localization, reduced
phosphorylation and weakened interaction with clathrin. The most striking feature of
the F525A cells however is a marked shortening of mitosis, at least in part due to rapid
spindle assembly. F525A cells do not exhibit chromosome missegregation, indicating
that they undergo fast yet apparently faithful mitosis. By contrast, mutating the
phosphorylation site S558 to alanine in TACC3 causes aneuploidy without a significant
change in mitotic duration. Our work has therefore defined a regulatory role for the
Aurora-A-TACC3 interaction beyond the act of phosphorylation at S558. We propose
that the regulatory relationship between Aurora-A and TACC3 enables the transition
from the microtubule-polymerase activity of TACC3-ch-TOG to the microtubulecrosslinking
activity of TACC3-ch-TOG-clathrin complexes as mitosis progresses.
Aurora-A-dependent control of TACC3 could determine the balance between these
activities, thereby influencing not only spindle length and stability but also the speed of
spindle formation with vital consequences for chromosome alignment and segregation.